KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA^® (pembrolizumab), the company’s anti-PD-1 (programmed death receptor-1) therapy, for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (tumor proportion score [TPS] of 50 percent or more) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations. With this new indication, KEYTRUDA is now the only anti-PD-1 therapy to be approved in the first-line treatment setting for these patients. In addition, the FDA approved a labeling update to include data from KEYNOTE-010 in the second-line or greater treatment setting for patients with metastatic NSCLC whose tumors express PD-L1 (TPS of one percent or more) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. In metastatic NSCLC, KEYTRUDA is approved for use at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, KEYTRUDA (pembrolizumab) should be withheld or discontinued and corticosteroids administered when appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions and for Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see “Selected Important Safety Information” below.

“KEYTRUDA improved survival, compared to traditional chemotherapy, in patients with non-small cell lung cancer whose tumors express high levels of PD-L1,” said Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laboratories. “The approval of KEYTRUDA for the first-line treatment of metastatic non-small cell lung cancer has the potential to change the treatment landscape for these patients.”

“With this new indication, KEYTRUDA can now be a first treatment option instead of chemotherapy for patients with metastatic non-small cell lung cancer whose tumors express high levels of PD-L1,” said Roy S. Herbst, M.D., Ph.D., professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven. “These data reaffirm the importance of testing for PD-L1 expression in non-small cell lung cancer in order to identify those patients who are most likely to benefit from treatment with KEYTRUDA.”

Data Supporting First-Line Approval

The approval was based on data from KEYNOTE-024, a randomized, open-label, phase 3 study evaluating KEYTRUDA monotherapy compared to standard of care (SOC) platinum-containing chemotherapy for the treatment of patients with both squamous (18%) and non-squamous (82%) metastatic NSCLC. The study enrolled patients who had not received prior systemic chemotherapy treatment for their metastatic disease and whose tumors had high PD-L1 expression (TPS of 50 percent or more) and with no EGFR or ALK aberrations. The study randomized 305 patients to receive KEYTRUDA (200 mg every three weeks) or investigator-choice SOC platinum-based chemotherapy (pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin). Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies. The primary endpoint was progression-free survival (PFS); additional efficacy outcome measures were overall survival (OS) and overall response rate (ORR).

Based on an interim analysis demonstrating KEYTRUDA (pembrolizumab) was superior compared to chemotherapy for both the primary endpoint of PFS and the secondary endpoint of OS, the trial was stopped early in June 2016 to give patients still on chemotherapy the opportunity to receive KEYTRUDA.

Findings demonstrated that KEYTRUDA reduced the risk of progression or death by 50 percent compared to chemotherapy (HR, 0.50 [95% CI, 0.37, 0.68]; p<0.001). Additionally, KEYTRUDA resulted in a 40 percent reduction in the risk of death compared to chemotherapy (HR, 0.60 [95% CI, 0.41, 0.89]; p=0.005).

Efficacy Results from KEYNOTE-024
Endpoint		KEYTRUDA 200 mg every 3 weeks (n=154)		Chemotherapy   (n=151)
PFS
Number (%) of patients with event		73 (47%)		116 (77%)
Median in months (95% CI)		10.3 (6.7, NR)		6.0 (4.2, 6.2)
Hazard ratio* (95% CI)		0.50 (0.37, 0.68)
p-Value (stratified log-rank)		<0.001
OS
Number (%) of patients with event		44 (29%)		64 (42%)
Median in months (95% CI)		NR (NR, NR)		NR (9.4, NR)
Hazard ratio* (95% CI)		0.60 (0.41, 0.89)
p-Value (stratified log-rank)		0.005†
Objective Response Rate
ORR % (95% CI)		45% (37, 53)		28% (21, 36)
Complete response %		4%		1%
Partial response %		41%		27%
p-Value (Miettenen-Nurminen)		0.001
Median duration of response in months (range)		NR (1.9+, 14.5+)		6.3 (2.1+, 12.6+)

* Based on the stratified Cox proportional hazard model

† P-value is compared with 0.0118 of the allocated alpha for this interim analysis

NR = not reached

“The approval of KEYTRUDA in the first-line setting adds to the momentum of progress that has been made to treat lung cancer, particularly in the area of immunotherapy,” said Laurie Fenton Ambrose, president and CEO, Lung Cancer Alliance. “Patients now have an option beyond chemotherapy at initial diagnosis. This approval reinforces the need for biomarker testing so care can be personalized and most effective.”

Selected Important Safety Information for KEYTRUDA ^®  (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis. See additional “Selected Important Safety Information” below.

Data Supporting Second-Line Labeling Update

KEYNOTE-010 is a randomized, open-label, phase 2/3 trial evaluating KEYTRUDA (2 mg/kg [n=344] or 10 mg/kg [n=346] every three weeks) compared to SOC chemotherapy (docetaxel, 75 mg/m² every three weeks [n=343]) in 1,033 patients with squamous (21%) and non-squamous (70%) metastatic NSCLC with all levels of PD-L1 expression (TPS of one percent or more) who had progressed following platinum-containing chemotherapy and, if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Additionally, results were reported in a subset of patients who had high PD-L1 expression (TPS of 50 percent or more) in the KEYTRUDA 2 mg/kg (n=139), KEYTRUDA 10 mg/kg (n=151), and chemotherapy cohorts (n=152). The primary endpoints were OS and PFS. Additional efficacy measures included ORR and response duration.

KEYTRUDA demonstrated superior OS versus docetaxel in patients with all levels of PD-L1 expression. Based on exploratory analyses, higher OS was associated with higher PD-L1 expression level.

Efficacy Results from KEYNOTE-010: Subgroup of Patients with TPS of 50 Percent or More
Endpoint		KEYTRUDA 2 mg/kg every 3 weeks n=139		KEYTRUDA 10 mg/kg every 3 weeks n=151		Docetaxel 75 mg/m 2 every 3 weeks n=152
OS
Deaths (%)		58 (42%)		60 (40%)		86 (57%)
Median in months (95% CI)		14.9 (10.4, NR)		17.3 (11.8, NR)		8.2 (6.4, 10.7)
Hazard ratio* (95% CI)		0.54 (0.38, 0.77)		0.50 (0.36, 0.70)		---
p-Value (stratified log-rank)		<0.001		<0.001		---
PFS
Events (%)		89 (64%)		97 (64%)		118 (78%)
Median in months (95% CI)		5.2 (4.0, 6.5)		5.2 (4.1, 8.1)		4.1 (3.6, 4.3)
Hazard ratio* (95% CI)		0.58 (0.43, 0.77)		0.59 (0.45, 0.78)		---
p-Value (stratified log-rank)		<0.001		<0.001		---
Objective Response Rate
ORR† (95% CI)		30% (23, 39)		29% (22, 37)		8% (4, 13)
p-Value (Miettenen-Nurminen)		<0.001		<0.001		---
Median duration of response in months (range)		NR (0.7+, 16.8+)		NR (2.1+, 17.8+)		8.1 (2.1+, 8.8+)

* Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model

† All responses were partial responses

NR = not reached

Efficacy Results from KEYNOTE-010: All Randomized Patients with TPS of One Percent or More
Endpoint		KEYTRUDA 2 mg/kg every 3 weeks n=344		KEYTRUDA 10 mg/kg every 3 weeks n=346		Docetaxel 75 mg/m 2 every 3 weeks n=343
OS
Deaths (%)		172 (50%)		156 (45%)		193 (56%)
Median in months (95% CI)		10.4 (9.4, 11.9)		12.7 (10.0, 17.3)		8.5 (7.5, 9.8)
Hazard ratio* (95% CI)		0.71 (0.58, 0.88)		0.61 (0.49, 0.75)		---
p-Value (stratified log-rank)		<0.001		<0.001		---
PFS
Events (%)		266 (77%)		255 (74%)		257 (75%)
Median in months (95% CI)		3.9 (3.1, 4.1)		4.0 (2.6, 4.3)		4.0 (3.1, 4.2)
Hazard ratio* (95% CI)		0.88 (0.73, 1.04)		0.79 (0.66, 0.94)		---
p-Value (stratified log-rank)		0.068		0.005		---
Objective Response Rate
ORR† (95% CI)		18% (14, 23)		19% (15, 23)		9% (7, 13)
p-Value (Miettenen-Nurminen)		<0.001		<0.001		---
Median duration of response in months (range)		NR (0.7+, 20.1+)		NR (2.1+, 17.8+)		6.2 (1.4+, 8.8+)

* Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model

† All responses were partial responses

NR = not reached

In KEYNOTE-010, treatment was discontinued for adverse reactions in eight percent of the 682 patients receiving KEYTRUDA (pembrolizumab) across both doses. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA (pembrolizumab) occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most frequent adverse reactions (reported in at least 10% of KEYTRUDA patients and occurring at the same or higher incidence than in the docetaxel arm) were decreased appetite (25% for KEYTRUDA vs. 23% for docetaxel), dyspnea (23% vs. 20%), nausea (20% vs. 18%), cough (19% vs. 14%), rash (17% vs. 8%), constipation (15% vs. 12%), vomiting (13% vs. 10%), arthralgia (11% vs. 9%), back pain (11% vs. 8%), and pruritus (11% vs. 3%). Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%), and pyrexia (11%).

PD-L1 Companion Diagnostic for Patients with Metastatic NSCLC

The PD-L1 IHC 22C3 PharmDx™ kit made by Dako North America, Inc., an Agilent Technologies Company, was approved in 2015 by the FDA for use in detecting PD-L1, an immune-related biomarker expressed on some tumor cells. The diagnostic is intended to aid in identifying appropriate patients for treatment with KEYTRUDA, including previously treated patients whose tumors have any level of PD-L1 expression (TPS of one percent or more) and previously untreated patients whose tumors have high levels of PD-L1 expression (TPS of 50 percent or more). Tumors with a TPS of less than one percent are considered to have no PD-L1 expression.

About KEYTRUDA ^® (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA (pembrolizumab) is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (TPS ≥50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA ^®  (pembrolizumab) (continued)

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA (pembrolizumab), including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA can cause severe or life-threatening infusion-related reactions which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA (pembrolizumab) can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than docetaxel) were decreased appetite (25% vs. 23%), dyspnea (23% vs. 20%), and nausea (20% vs. 18%).

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 360 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For 125 years, Merck has been a global health care leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook, YouTube and LinkedIn.

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Please see Prescribing Information for KEYTRUDA (pembrolizumab) at  http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf  and

Patient Information/Medication Guide for KEYTRUDA at  http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf .